The Journal of clinical endocrinology and metabolism · 2024
Gene Expression Signatures Predict First-Year Response to Somapacitan Treatment in Children With Growth Hormone Deficiency.
Рандомизированное исследованиеКлиническое исследование III фазыСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Garner Terence, Clayton Peter, Højby Michael, Murray Philip, Stevens Adam
Аннотация
CONTEXT: The pretreatment blood transcriptome predicts growth response to daily growth hormone (GH) therapy with high accuracy.
OBJECTIVE: Investigate response prediction using pretreatment transcriptome in children with GH deficiency (GHD) treated with once-weekly somapacitan, a novel long-acting GH.
METHODS: REAL4 is a randomized, multinational, open-label, active-controlled parallel group phase 3 trial, comprising a 52-week main phase and an ongoing 3-year safety extension (NCT03811535). A total of 128/200 treatment-naïve prepubertal children with GHD consented to baseline blood transcriptome profiling. They were randomized 2:1 to subcutaneous somapacitan (0.16 mg/kg/week) or daily GH (0.034 mg/kg/day). Differential RNA-seq analysis and machine learning were used to predict therapy response.
RESULTS: 121/128 samples passed quality control. Children treated with somapacitan (n = 76) or daily GH (n = 45) were categorized based on fastest and slowest growing quartiles at week 52. Prediction of height velocity (HV; cm/year) was excellent for both treatments (out of bag [OOB] area under curve [AUC]: 0.98-0.99; validation AUC: 0.83-0.84), as was prediction of secondary markers of growth response: HV standard deviation score (SDS) (0.99-1.0; 0.75-0.78), change from baseline height SDS (ΔHSDS) (0.98-1.0; 0.61-0.75), and change from baseline insulin-like growth factor-I SDS (ΔIGF-I SDS) (0.96-1.0; 0.85-0.88). Genes previously identified as predictive of GH therapy response were consistently better at predicting the fastest growers in both treatments in this study (OOB AUC: 0.93-0.97) than the slowest (0.67-0.85).
CONCLUSION: Pretreatment transcriptome predicts first-year growth response in somapacitan-treated children with GHD. A common set of genes can predict the treatment response to both once-weekly somapacitan and conventional daily GH. This approach could potentially be developed into a clinically applicable pretreatment test to improve clinical management.
OBJECTIVE: Investigate response prediction using pretreatment transcriptome in children with GH deficiency (GHD) treated with once-weekly somapacitan, a novel long-acting GH.
METHODS: REAL4 is a randomized, multinational, open-label, active-controlled parallel group phase 3 trial, comprising a 52-week main phase and an ongoing 3-year safety extension (NCT03811535). A total of 128/200 treatment-naïve prepubertal children with GHD consented to baseline blood transcriptome profiling. They were randomized 2:1 to subcutaneous somapacitan (0.16 mg/kg/week) or daily GH (0.034 mg/kg/day). Differential RNA-seq analysis and machine learning were used to predict therapy response.
RESULTS: 121/128 samples passed quality control. Children treated with somapacitan (n = 76) or daily GH (n = 45) were categorized based on fastest and slowest growing quartiles at week 52. Prediction of height velocity (HV; cm/year) was excellent for both treatments (out of bag [OOB] area under curve [AUC]: 0.98-0.99; validation AUC: 0.83-0.84), as was prediction of secondary markers of growth response: HV standard deviation score (SDS) (0.99-1.0; 0.75-0.78), change from baseline height SDS (ΔHSDS) (0.98-1.0; 0.61-0.75), and change from baseline insulin-like growth factor-I SDS (ΔIGF-I SDS) (0.96-1.0; 0.85-0.88). Genes previously identified as predictive of GH therapy response were consistently better at predicting the fastest growers in both treatments in this study (OOB AUC: 0.93-0.97) than the slowest (0.67-0.85).
CONCLUSION: Pretreatment transcriptome predicts first-year growth response in somapacitan-treated children with GHD. A common set of genes can predict the treatment response to both once-weekly somapacitan and conventional daily GH. This approach could potentially be developed into a clinically applicable pretreatment test to improve clinical management.